Invasive prostate cancer continues to be a fatal disease, indicating that effective treatment modalities must be identified. Interestingly, we discovered that several retinoid X receptor (RXR) ligands (rexporters) potentiate the egress of the TR3/RXRalpha nuclear receptor heterodimer from the cancer cell nucleus to its mitochondria to facilitate apoptosis induced by several anti-prostate cancer drugs both in vitro and in vivo. Thus, both RXR and TR3 have extra nuclear functions. Export of TR3 requires RXR. The TR3/RXRalpha apoptosis pathway also involves the interaction of TR3 with mitochondrial surface-associated Bcl-2. On interacting with TR3, Bcl-2 undergoes a conformational change that reverses Bcl-2 function from a cell-protective protein to one supporting apoptosis involving the release of cytochrome c and the initiation of the caspase cascade. We hypothesize that because both TR3 and Bcl-2 are often overexpressed in prostate cancers, rexporters, which potentiate their interaction, in combination with apoptotic anti-prostate cancer drugs should have enhanced efficacy. We propose improving the therapeutic index (activity versus toxicity) of these rexporters by integrating synthesis with design guided by four major aims as follows: (1) Computational Studies. Identify more selective rexporters through novel computational studies involving rapid virtual structural database docking to RXRalpha complemented by pharmacophore construction. (2) Rexporter Synthesis. Enhance efficacy and TR3/RXR selectivity to reduce retinoid adverse effects by introducing new scaffolds and substituents based on Aims 1,3, and 4 results. (3) Role of TR3/RXRalpha in chemotherapy-induced prostate cancer apoptosis. Examine the role of RXR and its ligands in regulating TR3 activities through TR3/RXRalpha heterodimerization. Determine how rexporters enhance chemotherapeutic drug-induced prostate cancer apoptosis. (4) In vitro/In vivo Studies. Evaluate rexporter anticancer efficacy in vitro alone and in combination with an apoptotic anti-prostate cancer drug such as etoposide. The most efficacious rexporter-drug combinations in vitro will be evaluated in a prostate cancer xenograft model, and those active in vivo verified in the TRAMP mouse model. Synergistic/additive in vitro effects will be determined using isobologram methods. These studies will enhance our understanding of the molecular mechanisms underlying the anti-prostate cancer activity of chemotherapeutic drugs and the roles of TR3/RXRalpha and rexporter ligands in this process. We anticipate that our results will provide a more effective and less systemically toxic means of enhancing the efficacy of chemotherapeutic agents currently used to treat prostate cancer.